JPH04261119A - Percutaneous absorption-type pharmaceutical preparation - Google Patents

Abstract

PURPOSE:To provide percutaneous absorption-type cataplasm excellent in the percutaneous absorbability for pharmaceutically active substances, good in the stability with the elapse of time of the absorbability because of no crystallization of the substances, also having characteristics such as good adherability. CONSTITUTION:The objective pharmaceutical preparation with an adhesivity of >=25g/12mm, comprising a composition which can be obtained by incorporating (A) 100 pts.wt. of a polymer made up of (1) lipophilic monomer unit and (2) hydrophilic monomer unit at the weight ratio (98:2)-(0:100) with (B) pharmaceutically active substance (s), (C) 5-100 pts.wt. of an alcohol, (D) 0-50 pts.wt. of a percutaneous absorption promoter and (E) 0-50 pts.wt. of water.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention is a novel transdermal absorption type preparation,
More specifically, it has excellent transdermal absorption of pharmacologically active substances, and is effective for the treatment of various diseases in which desired pharmacologically active substances can be rapidly delivered to local sites or throughout the body through the circulatory system.
The present invention relates to a transdermal preparation suitable for use as a transdermal patch.

0002

[Prior Art] In recent years, in the medical field, transdermal absorption-type preparations have been developed that can deliver desired pharmacologically active substances throughout the body through the skin and exhibit therapeutic effects over a long period of time.
For example, transdermal absorption preparations using nitroglycerin and isosorbide nitrate for the treatment of angina, clonidine for the treatment of hypertension, and estradiol for the treatment of menopausal disorders as the pharmacologically active substances have been put into practical use. however,
Although these transdermal absorption preparations have many advantages, such as avoiding the metabolism of pharmacologically active substances in the intestines and liver, reducing side effects, and improving the durability of drug efficacy, the skin is inherently susceptible to foreign substances entering from the outside. As a result, there are only a limited number of pharmacologically active substances whose blood concentration reaches an effective therapeutic range through transdermal absorption. There is a drawback that there is no Therefore, various methods have been attempted to improve the percutaneous absorption of pharmacologically active substances. For example, methods such as prodrug formation and complex formation by modification of pharmacologically active substances, and iontophoresis for ionic pharmacologically active substances have been attempted;
All of these methods require careful consideration of each pharmacologically active substance, and have the problem of requiring a lot of time and a large amount of investment. On the other hand, the development of absorption enhancers that improve the transdermal absorption of pharmacologically active substances by lowering the barrier properties of the skin has been actively conducted. It cannot be said that both absorption promotion effect and safety are necessarily satisfied, and many pharmacologically active substances have shortcomings such as long lag time and long time required for the onset of pharmacological action in transdermal absorption. have. On the other hand, the dosage forms of transdermal preparations include, for example, patches, ointments, creams, gels, lotions, liquids, and sprays, among which patches are the most commonly used. It is widely used because of its ease of use and long-lasting medicinal effects. This transdermal patch has a structure in which an adhesive layer in which a pharmacologically active substance is dissolved or dispersed is provided on a flexible support, but the percutaneous absorption of the pharmacologically active substance is low, and It has drawbacks such as the limited number of applicable pharmacologically active substances. Therefore, various attempts have been made to improve these drawbacks, and for example, transdermal patches have been disclosed that have improved transdermal absorbability by increasing the concentration of pharmacologically active substances in the adhesive. (Japanese Unexamined Patent Publication No. 185713/1983, No. 93714/1983). However, in the transdermal patch,
The effect of improving transdermal absorbability is not necessarily sufficient, and depending on the type of pharmacologically active substance, there is a problem that the transdermal absorbability may change over time due to crystallization.

0003

[Problems to be Solved by the Invention] The present invention overcomes the drawbacks of conventional transdermal absorption patches, improves the transdermal absorption of pharmacologically active substances, and improves the types of pharmacologically active substances that can be applied. The purpose of this project is to provide a transdermal preparation that increases the number of transdermal agents and that does not cause changes in transdermal absorbability over time due to crystallization, and is suitable for use as a transdermal patch. .

0004

[Means for Solving the Problems] The present inventors have conducted intensive research to develop a transdermal absorption type preparation having the above-mentioned favorable properties. The inventors discovered that a transdermal preparation consisting of a composition containing a certain amount of alcohol, an optional transdermal absorption enhancer, and water was suitable for the purpose, and based on this knowledge, they completed the present invention. I ended up doing it.

That is, the present invention provides lipophilic monomer units and hydrophilic monomer units in a weight ratio of 98:2 to 0:1.
A pharmacologically active substance is added to a high molecular weight polymer containing 5 to 10 parts of alcohol per 100 parts by weight of the polymer.
0 parts by weight, 0 to 50 parts by weight of transdermal absorption enhancer, and 0 to 5 parts by weight of water.
At least 25 g of the composition containing 0 parts by weight
The present invention provides a transdermal absorption type preparation having an adhesive force of /12 mm.

The present invention will be explained in detail below.

[0007] In the transdermal absorption type preparation of the present invention, a high molecular weight polymer containing lipophilic monomer units and hydrophilic monomer units in a specific ratio is used as the polymer material. The lipophilic monomer is preferably an acrylic ester monomer, such as acrylic acid or methacrylic acid and an alcohol having 1 to 14 carbon atoms, specifically methanol, ethanol, n-propanol, isopropanol, n-butanol, isopropanol, or methacrylic acid. Butanol, n-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 3-methyl-1-butanol, 1-methyl-1
-pentanol, 2-methyl-1-pentanol, 3-
Methyl-1-pentanol, 2-ethyl-1-butanol, 3,5,5-trimethyl-1-hexanol, 3-
Mention may be made of esters obtained from heptanol, 2-ethylhexanol, n-decanol, lauryl alcohol, and the like. These lipophilic monomers may be used alone or in combination of two or more.

On the other hand, examples of hydrophilic monomers include (
meth)acrylic acid, itaconic acid, maleic acid, 2-hydroxy(meth)acrylate, 2-hydroxypropyl(meth)acrylate, 3-hydroxypropyl(meth)acrylate, diethylene glycol(meth)acrylate, triethylene glycol(meth)acrylate , polyethylene glycol (meth)acrylate, dipropylene glycol (meth)acrylate, tripropylene glycol (meth)acrylate, polypropylene glycol (meth)acrylate, trimethylolpropane (meth)acrylate, tetramethylolmethane (
meth)acrylate, pentaerythritol (meth)acrylate, glycerin (meth)acrylate, (meth)acrylamide, N,N-dimethylacrylamide,
Examples include N-vinylpyrrolidone and vinyl ethers, but among these, those with the general formula

0009
]

[Case 2]

Compounds represented by (wherein R is a hydrogen atom or a methyl group, n is an integer from 1 to 5), such as 2-hydroxyethyl (meth)acrylate, diethylene glycol (meth)acrylate, triethylene glycol (Meth)acrylate etc. are suitable. One type of the hydrophilic monomer may be used, or two or more types may be used in combination.

The content ratio of the lipophilic monomer unit and the hydrophilic monomer unit in the polymer is 98:2 by weight.
The range is selected from 0:100 to 0:100. If the amount of the hydrophilic monomer unit is less than the above range, the effect of improving transdermal absorbability will not be sufficiently exhibited. The preferred ratio is in the range of 90:10 to 60:40, but the object of the present invention can be fully achieved in the case of polyvinyl ether, which has a low glass transition point among hydrophilic monomer homopolymers.

[0012] In the production of the polymer, a crosslinking monomer is usually used in addition to the lipophilic monomer and hydrophilic monomer described above. As this crosslinking monomer,
Compounds having at least two polymerizable double bonds, such as ethylene glycol di(meth)acrylate, propylene glycol di(meth)acrylate, trimethylolpropane tri(meth)acrylate, polyethylene glycol di(meth)acrylate, polypropylene glycol di(meth)acrylate, Examples include meth)acrylate, tetramethylolmethanetetra(meth)acrylate, pentaerythritol tri(meth)acrylate, glycerin di(meth)acrylate, dipentaerythritol hexa(meth)acrylate, and divinylbenzene. These crosslinking monomers are usually used in a proportion of 0.01 to 1 mol % based on the total amount of the lipophilic monomer and the hydrophilic monomer.

There are no particular restrictions on the method for producing the polymer, and the method conventionally used in the production of acrylic resins can be used, for example, by adding benzyl to a mixture of the lipophilic monomer, hydrophilic monomer and crosslinking monomer in a predetermined proportion. After adding a photopolymerization initiator such as dimethyl ketal, photopolymerization is carried out by irradiating it with ultraviolet rays, or by adding azobisisobutylene to a mixture of the lipophilic monomer, hydrophilic monomer, and crosslinking monomer in a predetermined ratio. A method of adding a radical polymerization initiator such as lonitrile and then carrying out heating polymerization can be used. Other manufacturing methods include adding a crosslinking agent such as a polyfunctional isocyanate, epoxy resin, or metal chelate compound to a solvent solution of an uncrosslinked polymer obtained by polymerizing lipophilic monomers or hydrophilic monomers, and heating the mixture. be able to.

There are no particular restrictions on the pharmacologically active substance to be contained in the polymer thus obtained, and any pharmacologically active substance can be selected from conventionally known pharmacologically active substances. The pharmacologically active substances include, for example, steroidal anti-inflammatory agents such as prednisolone, dexamethasone, hydrocortizone, fluocinoloacetonide, betamethasone valerate, betamethasone dipropionate, indomethacin, diclofenac, ibufenac, ibuprofen, ketoprofen, flufenamic acid, Nonsteroidal anti-inflammatory agents such as mefenamic acid, phenylbutazone, methyl salicylate, and sodium salicylate; antihistamines such as diphenhydramine, chlorpheniramine, promethazine, and tripelenamine; and central nervous system agents such as chlorpromazine, nitrazepam, diazepam, phenobarbital, and reserpine. , hormones such as insulin, testosterone, methyltestosterone, progesterone, and estradiol, clonidine, reserpine,
Antihypertensive agents such as guanethidine sulfate, inotropes such as dichotocin and dicoxin, antiarrhythmic agents such as propranol hydrochloride, procainamide hydrochloride, ajmaline, and pindolol, nitroglycerin, isosorbide dinitrate, erythritol tetranitrate, papaverine hydrochloride, Coronary vasodilators such as nifedipine, local anesthetics such as lidocaine, benzocaine, and procaine hydrochloride, hypnotics and sedatives such as barbital, thiopental, phenobarbital, and cyclobarbital, and analgesics such as morphine, aspirin, codeine, acetanilide, and aminopyrine. , antibiotics such as penicillin, tetracycline, erythromycin, streptomycin, gentamicin, antifungal agents such as benzalkonium chloride, acetophenylamine, nitrofurazone, bentamycin, naphthiomate, 5-fluorouracil, busulfan, actinomycin, bleomycin, mitomycin, etc. Anti-neoplastic agents, hydrochlorothiazide, penflutide,
Anti-pressure diuretics such as reserpine, parasympatholytic agents such as scopolamine and atropine, antiepileptic drugs such as nitrazepam and meprobamate, anti-Pekinson's disease drugs such as chlorzoxazone and levodopa, sulfamine, sulfamonomethoxine, sulfamethizole, etc. sulfa drugs,
Further examples include, but are not limited to, vitamins, prostaglandins, and anticonvulsants. One type of these pharmacologically active substances may be used, or two or more types may be used in combination.

In the present invention, it is necessary that the polymer contains an alcohol together with these pharmacologically active substances. Examples of the alcohols include ethyl alcohol, n-propyl alcohol, isopropyl alcohol, ethylene glycol, and propylene glycol. These alcohols may be used alone, in combination of two or more, or in combination with water. The amounts of alcohol and water to be used are selected within the range of 5 to 100 parts by weight and 0 to 50 parts by weight, respectively, per 100 parts by weight of the polymer.

In the present invention, the polymer may contain a transdermal absorption enhancer, if desired, along with the pharmacologically active substance, alcohol, and optionally water. There are no particular restrictions on the transdermal absorption enhancer, and compounds conventionally known as transdermal absorption enhancers, such as polar solvents such as dimethyl sulfoxide, decylmethyl sulfoxide, dimethylformamide, and dimethylacetamide, azacycloheptan-2-one, etc. cycloalkanes, esters of alcohol and carboxylic acid such as isopropyl myristate, isopropyl palmitate, and diethyl sebacate, glycols and surfactants such as sodium lauryl sulfate, oils and fats such as olive oil, squalene, and lanolin, and skin. Natural moisturizing factors such as fatty acids, pyroglutamic acid and urea derivatives, fatty acid mono- or diethanolamides, D-limonene, L-limonene, etc. are included, and among these, D-limonene is particularly preferred. One type of these transdermal absorption enhancers may be used, or
Two or more types may be used in combination, and the amount used is as follows:
The amount is selected from 0 to 50 parts by weight per 100 parts by weight of the polymer.

[0017] The transdermal absorption type preparation of the present invention comprises a composition in which the above-mentioned polymer contains a pharmacologically active substance, an alcohol, an optionally used transdermal absorption enhancer, and water. There are no particular restrictions on the method for preparing this composition; for example, the polymer is added to a solution containing a desired pharmacologically active substance, an alcohol, an optional transdermal absorption enhancer, and water in predetermined proportions. A method of impregnating the solution into the polymer by immersing the polymer can be used. In addition, other adjustment methods include uncrosslinked polymers,
A method can also be used in which a solution of a crosslinking agent, a desired pharmacologically active substance, an alcohol, an optional transdermal absorption enhancer, and water mixed in a predetermined ratio is cast into a sheet and then heated.

[0018] If desired, various pharmacologically acceptable additives such as stabilizers, anti-aging agents, antioxidants, fragrances, fillers, etc. may be added to the composition within a range that does not impair the purpose of the present invention. be able to.

The transdermal absorption type preparation of the present invention comprising the composition thus prepared has excellent percutaneous absorption of pharmacologically active substances, and since the pharmacologically active substances do not crystallize, There is no change in skin absorbability over time,
Moreover, it has good adhesion, with an adhesive strength of 25 g/12 mm or more, measured in accordance with the adhesive strength test for bandages in the Japanese Pharmacopoeia manual.

The transdermal preparation of the present invention is suitably used as a transdermal patch. This transdermal absorption patch is made by, for example, providing a layer of the composition with a thickness of about 10 to 1000 μm on a suitable base material, and then applying a release film treated with a silicone resin or the like on top of this layer. It can be produced by bonding them together so that their surfaces are in contact. Examples of base materials used in this case include sheets and films made of synthetic resins such as polyester, polyvinyl chloride, polypropylene, polyethylene, and polyurethane, synthetic paper, cellulose sheets and films, and nonwoven fabrics made of various materials. Examples include woven fabrics and knitted fabrics.

[0021]

EXAMPLES Next, the present invention will be explained in more detail with reference to examples, but the present invention is not limited to these examples in any way.

[0022] The performance of the transdermal preparation was evaluated as follows.

(1) Adhesive Strength Adhesive strength was determined in accordance with the adhesive strength test for adhesive plasters in the Japanese Pharmacopoeia Manual.

[0024] That is, from the tape type patch, the width is 12 m.
After cutting out a test piece with a length of 250 mm and peeling off the release film, one end was placed on a phenolic resin test plate with a width of about 25 mm, a length of 125 mm, and a thickness of 5 mm, which had been left in a thermostat at 37°C for 30 minutes. Immediately apply a rubber roller weighing 850g on top of this.
Two passes are made at a speed of 300 mm per minute. This is 37℃
After leaving it in a thermostat for 30 minutes, fold the free end attached to the test plate at a 180° angle and place it about 25 m from the tip of the test plate.
After peeling off the test piece, using a tensile testing machine, the free end of the test piece was placed on the top and the test plate was placed on the bottom with a clamp, and the test pieces were continuously peeled off at a speed of 300 mm for 1 minute, 4 times at intervals of about 20 mm. The loads were measured and the average value was determined.

(2) Cut a 3.14 cm 2 test piece from the transdermal absorbable tape-type patch and peel off the release film.

On the other hand, male Wistar rats 180-20
After removing 0 g of abdominal hair with an animal clipper, the test piece was applied, and after 2, 4, 6, and 8 hours, 0.3 ml of blood was collected from the scapular vein to determine the drug concentration in the blood. It was quantified by high performance liquid chromatography to evaluate transdermal absorbability.

Example 1 After adding 0.1 mol% of trimethylolpropane triacrylate and 1 mol% of benzyl dimethyl ketal as a photopolymerization initiator to a mixture of 60 parts by weight of 2-ethylhexyl acrylate and 40 parts by weight of acrylic acid. After replacing the dissolved oxygen with nitrogen, the mixture was poured into a container with a depth of 1 mm, and then irradiated with ultraviolet rays (under a nitrogen gas atmosphere) to obtain a crosslinked polymer.

Next, the remaining monomer was extracted with methanol and chloroform to purify the polymer, which was then dried under reduced pressure.

The purified polymer was immersed in a solution consisting of 10 parts by weight of ketoprofen as a model drug, 60 parts by weight of ethanol, and 30 parts by weight of water to form a composition containing 40 parts by weight of a water-ethanol solution of the drug. A transdermal formulation was prepared.

[0030] Next, a 50 μm thick layer of the transdermal preparation was provided on a 25 μm thick polyester film, and then a 38 μm thick layer with one side treated with silicone resin was formed.
A tape-type adhesive patch was prepared by laminating a polyester film for peeling (m), and its adhesive strength and transdermal absorbability were determined.

Example 2 A tape-type patch was prepared in the same manner as in Example 1, except that 2-hydroxyethyl acrylate was used instead of acrylic acid, and its performance was evaluated.

Example 3 A tape-type patch was prepared in the same manner as in Example 1 except that N-vinylpyrrolidone was used instead of acrylic acid, and its performance was evaluated.

Example 4 A tape-type patch was prepared in the same manner as in Example 1, except that diethylene glycol methacrylate was used instead of acrylic acid, and its performance was evaluated.

Example 5 A tape-type patch was prepared in the same manner as in Example 1 except that N,N-dimethylacrylamide was used instead of acrylic acid, and its performance was evaluated.

Example 6 Example 1 was repeated except that ethyl acrylate was used instead of 2-ethylhexyl acrylate and diethylene glycol methacrylate was used instead of acrylic acid.
A tape-type patch was prepared in the same manner as in Example 1, and its performance was evaluated.

Example 7 A tape-type patch was prepared in the same manner as in Example 6, except that butyl acrylate was used instead of ethyl acrylate, and its performance was evaluated.

Example 8 A tape-type patch was prepared in the same manner as in Example 6, except that lauryl acrylate was used instead of ethyl acrylate, and its performance was evaluated.

Example 9 A tape-type patch was prepared in the same manner as in Example 6, except that 30 parts by weight of ethyl acrylate and 30 parts by weight of lauryl acrylate were used instead of 60 parts by weight of ethyl acrylate. , and evaluated its performance.

Examples 10 to 18 Tape-type patches were prepared in the same manner as in Examples 1 to 9, except that 4 parts by weight of D-limonene (transdermal absorption enhancer) was further added to the formulations of Examples 1 to 9. was fabricated and its performance was evaluated.

Example 19 A tape-type patch was prepared in the same manner as in Example 1, except that 90 parts by weight of ethanol alone was used instead of 60 parts by weight of ethanol and 30 parts by weight of water.
Its performance was evaluated.

Comparative Example 1 The transdermal preparation prepared in Example 1 was dried at 100°C for 3 minutes, and then dried under reduced pressure for 1 day and night to remove water-ethanol and prepare a preparation containing only ketoprofen. A tape-type patch was prepared in the same manner as in Example 1, and its performance was evaluated.

Comparative Example 2 An ethyl acetate solution containing 40% by weight of a copolymer obtained from 40 parts by weight of 2-ethylhexyl acrylate, 55 parts by weight of butyl acrylate, and 5 parts by weight of acrylic acid was prepared, and the copolymer was added to this solution. Per 100 parts by weight (solid content) of the combined
Adding 4 parts by weight of ketoprofen as a model drug,
Stirred.

Next, it was applied onto a polyester film with a thickness of 25 μm so that the thickness after drying was 50 μm.
After drying at 90°C for 3 minutes, the residual solvent was removed by vacuum drying, and then a 38 μm thick release polyester film treated with silicone resin on one side was bonded to create a tape-type patch, and its performance was evaluated. evaluated.

Comparative Example 3 A tape-type patch was prepared in the same manner as in Example 1, except that 110 parts by weight of ethanol alone was used instead of 60 parts by weight of ethanol and 30 parts by weight of water. Its performance was evaluated.

These results are shown in Table 1.

Table 1 Adhesive strength
Blood concentration (ng/ml)
(g/12mm) 2hr 4hr
6hr 8hr Example 1 1
30 630 770 780
870 Example 2 125
540 330 770 1010
Example 3 215 300
430 290 280 Example 4
200 710 880 10
50 1410 Example 5 285
520 420 700 66
0 Example 6 75 220
440 340 360 Example 7 125 490 810
1420 1650 Example 8 195
900 1250 2310 235
0 Example 9 180 1940 1
890 2980 3040 Example 10
145 1430 1510 2050
1950 Example 11 140
720 930 950 1070
Example 12 225 1210 126
0 1550 2040 Example 13 1
95 1310 2340 2820 2
790 Example 14 275 48
0 520 740 890 Example 15 80 1850 408
0 4860 5340 Example 16 1
40 1820 2550 3300 3
230 Example 17 185 2650
3840 3970 4120 Example 18
140 3430 3030 42
70 4360 Example 19 45
720 930 950 10
30 Comparative example 1 315 140
190 170 210 Comparative example 2 410 200 250
230 240 Comparative example 3
0 590 320 27
0 290

As can be seen from Table 1, all of the transdermal absorption preparations of the present invention exhibit higher blood concentrations than those of the comparative examples.

Furthermore, ordinary acrylic pressure-sensitive adhesives become tack-free when exposed to water, but by increasing the content of hydrophilic monomer units, a composition with good adhesive properties can be obtained even if it contains water-ethanol. It will be done.

[0049]

Effects of the Invention The percutaneously absorbable preparation of the present invention contains a copolymer of a lipophilic monomer and a hydrophilic monomer, an alcohol,
It consists of a composition containing a pharmacologically active substance, a transdermal absorption enhancer used in some cases, and water, and has excellent transdermal absorption, can be applied to many types of pharmacologically active substances, and contains a pharmacologically active substance. Since it does not crystallize, it has good stability over time for transdermal absorption and also has good adhesive properties, so it is suitably used as a transdermal absorption patch.

Claims (2)

[Claims] Claim 1: A high molecular weight polymer containing lipophilic monomer units and hydrophilic monomer units in a weight ratio of 98:2 to 0:100, a pharmacologically active substance, and alcohol per 100 parts by weight of the polymer. 1. A transdermal absorption preparation having an adhesive strength of at least 25 g/12 mm, comprising a composition containing 5 to 100 parts by weight of a transdermal absorption promoter, 0 to 50 parts by weight of a transdermal absorption enhancer, and 0 to 50 parts by weight of water. 2. The transdermal preparation according to claim 1, wherein the hydrophilic monomer is a compound represented by the general formula: [Image Omitted] (R in the formula is a hydrogen atom or a methyl group).